Pyridino compounds and their production



UNITED STATES,

PYRIDINO COMPOUNDS ANDTHEIR PRODUCTION Max Albert Kunz, Mannheim, andGer-d Kochendoerfer and Karl Koeberle, Ludwigshafemonthe-Rhine,.Germany, assignors to I. G. Farbenindustrie Aktiengesellsohaft,Frankfort-onthe-Main, Germany N Drawing. 0 0 Application December ,24,1931,

Serial No. 583,144. In Germany December 27,

scams. (01. 260-40) The present invention relates to pyrldino compoundsof thearomaticseriesand process of producing the same. 0

Skraups synthesis for the preparation of quinoline,its homologues,analogues and substitution 0 products thereof from aromatic amines bytreatment with glycerine, and sulphuric acid with an addition ofnitrobenzene or other oxidizing agents has hitherto been employedindustrially to but 0 a very slight extent in spite of numerous proposedeneoxide and the 'p'rimuline bases.

modifications, in partdue to the violence of the reaction and theusually small yields.

We have now found that, contrary to'expectation, by carrying out theSkraup reaction by meansof glycerine in the presence ofan oxidizingagent in sulphuric acid from about 40 to .75

. such. 0 The process according tothe present invention may be employedto produce pyridino compounds from the amines of one, two or threeringedisoor heterocyclic aromatic compounds which, however, in the caseofthree-ringed isocyclic compounds should not containketo'groups inpara-position to each other. Amines which may be used for the purpose ofthe invention are, for example, monoand poly-amino compounds derivedfrom benzene, its homologues and substitution products, for example,aniline, toluidine, halogenanilines, nitranilines, halogennitranilines,carboxylicand sulphonic acids of the said amino compounds, phenylenediamine and its substitution products, the amines of naphthalene and itssubstitution products, aminofluorenes, aminoan- "thacenes,aminophenanthrenes. Suitable amines of the heterocyclic series are, forexample, those derived from pyridine, quinoline, naphthoquinoline,acridine, naphthostyril, carbazole," diphenyl- Instead of the. freeamines, derivatives thereof substituted on the nitrogen atom which underthe working conditions are converted into the amines may be used, forexample the N-acyl compounds, such as the acetyl, .benzoyl and similarcompounds, or azornethines may be employed as starting mate. rials. Asoxidizing agents may be mentioned aromatic nitro compounds, inparticular nitrobenzene, preferably in the form of its sulphonic acids,and arsenic acid. The addition ,ofsubstances assisting oxidation hasproved advantageous for which purpose vanadium pentoxide and selenicoxide may be used. a 0

As regards the economy of the process, it is important that distilledglycerine need not be employed, but that the crude glycerine containingwater obtained by the cleavage of fats (saponificate) may be employedequally well. 1

The following examples will further illustrate the nature of thisinvention but the invention is 10 not restricted to these examples. Thepartsare by weight.

. Ezrample 1 180 parts of nitrobenzene are sulphonated by 151 warming ona waterbath for a short time with 650 parts of 23 per cent oleum untilunchanged nitrobenzene cannot any more be detected when diluting asample with water. After cooling, 300 parts of water, 100 parts ofaniline and 260 parts of 90 per cent aqueous glycerine are added and thewhole is heated to boiling whilestirring under a reflux condenser. Theboiling point of the homogeneous, quietly boiling liquid is 138 C. andit falls to 127 C. during the conversion which 25 lasts from about 6 to7. hours. After that time, the separation of oxy metanilic acid in acrystalline formis observed. The mixture is diluted with about the samevolume of-water, the metanilic acid is filtered off by suction aftercooling, a little sodium nitrite is added to decompose any aniline whichhas not been quiteconverted, thewhole is made alkaline and the quinolineisdistilled off with steam. The distillateis extracted with ether, theether solution dried over caustic potash and the oil remaining afterexpelling the ether is dis tilled. A small amount of first runnings isobtained and then the quinoline. passes over at from 229 to 230 C. in anamount of 106 parts.

Example 2 V parts of 23 per cent oleum as described in Example 1 in avessel lined with lead and after cooling, 110 parts of Water, parts ofaniline and 150 parts of an aqueous saponificate (crude glycerine)containing from about to per cent glycerin'e are introduced and themixture heated. The liquid commences to boil quietly at C. and thetemperature falls to, from 128 to 12.9 0. within the course of from 6 to'7 hours. The whole is allowed to cool, about the same volume of wateris added and the separated oxymetanilic acidis filtered 01f by suction.Milk of l me i5 added to the hot filtrate until the reac- A mixture of40 parts of aniline, 210 parts of a 69 per cent sulphuric acid, parts ofdehydrated glycerine and 50 parts or" sodium nitrobenzene sulphonate isheated under a reflux condenser while stirring. The mixture commences toboil quietly at 139 C. and the temperature falls to 128 C. during thecourse of 'lhours while the metanilic acid formed gradually separatesout. The reaction mixture is worked up as described in Example 1.

Example 4 54 parts of para-toluidine are dissolved in 750 parts of a 64per cent sulphuric acid and 200 parts of sodium nitrobenzenesulphonateand 1'70 parts of 90 per cent aqueous glycerine areintroduced. The whole is heated to boiling under a reflux condenser, thetemperature being C. and falling to 130 C. during the course of 4 hours.The further working up is carried out in the manner described inExample 1. The yield of 6- methylquinoline is 57 parts.

Example 5 100 parts of ortho-chloraniline are boiled gently in 800 partsof sulphuric acid of 66 per cent strength with 200 parts of nitrobenzenesulphonic acid and parts of about 90 per cent aqueous glycerine whilestirring until a sample no longer contains unchanged initial material(for example until a sample is no longer diazotizable) which is usuallythe case after 2 hours. The whole is then allowed to cool, is dilutedwith water, made alkaline and distilled with steam. After the reactionproduct has'been separated in the usual manner, it is dried. The yieldis from about 100 to 107 parts of B-chlorquinoline, i. e. about 82 percent of the theoretical yield.

From para-chloraniline, 6-chlorquinoline is obtained in a similar manneras a pale green yellow oil which solidifies to almost colorlesscrystals.

. 2,5-dichloraniline, when treated with glycerine, sulphuric acid of theaforesaid concentration and nitrobenzene sulphonic acid. yields5.8-dichlorquinoline in very good yields. This compound crystallizes inthe form of long colorless needles.

Example 6 54 parts of Z/l-dichloroaniline are dissolved in 750 parts ofa 64 per cent sulphuric acid, parts of sodium nitrobenzene sulphonateand 140 parts of 90 per cent aqueous glycerine are introduced and themixture is heated to boiling. After several hours, when the boilingpoint no longer decreases, the whole is diluted with water, freed fromsmall amounts of impurities by filtration and the filtrate is madealkaline. The 6,8-dichlorquinoline, which separates out in anexcellently pure state, may be crystallized from alcohol. It is obtainedin a yield of 55 parts in the form of a colorless crystal powder.

Example 7 20 parts of 3,4,5-trichloraniline are dissolved in 200 partsof'66 per cent sulphuric acid while stirring at from 80 to 90 C. 40parts of nitrobenzene sulphonic acid and 30 parts of 90 per cent aqueousglycerine are then added and the whole is heated to boiling until thereaction is completed. The reaction mixture is then allowed to cool,diluted, made alkaline and the reaction product which separates in acrystalline form is filtered on" by suction. The yield of5,6,7-trichlorquinoline amounts to 98 per cent of the theoretical yield.It crystallizes from glacial acetic acid'in the form of colorlessneedles which are practically insoluble in water.

5,6,8-trichlorquinoline is obtained in an analogous manner from2,4,5-trichloraniline.

By the same process, 4-nitro-2-chloraniline yields6nitro-8chlorquinoline which crystallizes in the form of yellowishneedles.

Instead of the chloro derivatives, the corresponding bromanilines oriodoanilines may be converted into the corresponding quinolines.

Example 8 50 parts of para-nitraniline are dissolved in 700 parts ofsulphuric acid of 69 per cent strength and heated to boiling for severalhours while stirring with 120 parts of 90 per cent aqueous glycerine and200 parts of an aqueous arsenic acid containing about 80 per cent ofH3AsO4. The initial temperature of 139 C. falls to about 134 C. Thereaction mixture is diluted with water, freed from small amounts ofimpurities by filtration and made alkaline whereby the 6-nitroquinolineseparates in the form of grey crystals. It is filtered off by suction,washed until neutral and may, if desired, be crystallized from alcoholwith an addition of animal charcoal, whereby it is obtained in an amountof 45 parts in a pure white form.

Orthoand meta-nitram'lines may also be converted into the correspondingquinolines in a similar manner.

Example 9 100 parts of para-amido benzoic acid are dissolved in 1500parts of 64 per cent sulphuric acid.

300 parts of 90 per cent aqueous glycerine and 300 parts of sodiumnitrobenzene sulphonate are added and the mixture is boiled for fromabout 5 to 6 hours under a reflux condenser. After dilution with thesame amount of water, the mixture is filtered, made slightly alkaline,shaken well with animal charcoal and filtered. Acetic acid is then addedwhereby the quinoline-6-carboxylic acid is precipitated in the form ofsmall grey crystals. These are filtered off by suction, washed anddried. The yield is 85 parts. The acid may, if desired, be crystallizedfrom organic solvents.

Other phenylamino carboxylic acids may be converted into thecorresponding quinoline carboxylic acids in a similar manner.

Example 10 50 parts of para-para-diaminobenzophenone are suspended in600 parts of 66 per cent sulphuric acid. After adding 100 parts ofnitrobenzene sulphonic acid and '75 parts of 90 per cent aqueousglycerine, the reaction mixture is heated while stirring until it boilsgently. It is kept boiling gently for several hours and then allowedsulphuric acid.

a literature.

to cool, diluted withwaterfrenderedalkaline with caustic soda solution,the precipitate filtered by suction, washed until neutral and dried. Thecrystalline reaction product,'obtained in a practically quantitativeyield, namely ='dipyridinobenzophenone corresponding to the formula Bytreating para-para diaminodiphenylmethane with glycerine, arsenic acidand 66 per cent sulphuric acid, the; correspondingdipyridino-diphenylmethane derivative is obtained.

Erample ll 50 parts of para aminoacetanilide are suspended whilestirring in 600 parts of 66 per cent 100 parts of nitrobenzene sulphonicacid and 75 parts of 90 per cent aqueous glycerine are added, themixture is heated to boiling for several hours,allowed to cool, dilutedwith Water, made alkaline andthe reaction productwhich separatesin theform of lustrous silver s pangles is filtered ofi, by'suction. It may becrystallized from monochlorbenzene and is identical with thephenanthridine described in the Example 12 10 parts of fi-aminoquinolineare dissolved in 100 parts of 66 percent sulphuric acid. parts ofglycerine and parts of nitrobenzene sulphonic acid are added Whilestirring, the whole heated to boiling for from 2 to 3 hours, allowed tocool after the reaction is completed and worked up in the usual manner.The reaction product which separates in very good yields in the form oilustrous silver felt-like needles is identical with the phenanthridinedescribed in Example 11.

Example 13 12 parts of beta-naphthylamine are dissolved in 240 parts of64 percent sulphuric acid, 24 parts of aqueous glycerine (90 percentstrength) and 20 parts of sodium nitrobenzene sulphonate are added andthe whole heated to the boiling point for 4 hours under a refluxcondenser. After that v time, when the temperature has fallen from 138,

washed until neutral and the product is fused together'on a waterbath.After cooling, the super natant liquid is decanted and the solidcrystalline cake distilled invacuo. The beta-naphthoquinolinecorresponding to the formula line mass in a yield of from 12 to 13parts.

Alpha-naphthoquinoline isobtaincd in a similar manner fromalpha-naphthylamine and the corresponding dipyridinonaphthalene fromaminonaphthoquinoline.

Example 14 10 parts of aminonaphthostyril (prepared from naphthostyril(1,3-aminonaphthoic acid anhydride) by nitration and reduction) areheated to boiling in admixture with 220 parts of 64 per cent sulphuricacid, parts of aqueous glycerine 0128 Baum and 20 parts of sodiumnitrobenzene sulphonate. The'durationof the reaction is from 4 to 5hours. After cooling, the mixture is rendered slightlyiacid to congo bythe addition of, alkali, small amounts of resin are'filtered off andsodium acetate is added whereby the pyridinonaphthostyril which probablycorresponds to the formula:

is precipitated. It may bcobtained in the form of colorless crystals bycrystallization from trichlorbenzene. i

Example 15 v parts of 1"-amino 5-nitronaphthalene are dissolved in 300parts of per cent sulphuric acid'while heating. 50 parts of 90 per centaqueous glycerine and parts of nitrobenZene-metar sulphonic acid areintroduced. The mixture-is kept boiling gently for from 5 to 6 hoursand, after diluting with water,alkali is added until the reaction of thesolution is still acid to congo. Theprecipitate is filtered off and anexcess of alkali is added to .the' filtrate. The 5-nitro-1(N),Z-pyridino-naphthalene, an almost colorless solid substance, whichseparates is filtered off by suction and dried. It 'maybe obtained in acrystalline form from organic solvents, in which it .is readily soluble.

Example 16 65 parts of nitrobenzene sulphonic acid and '70 parts of percent aqueous glycerine are added to a solution of 20 parts of1,5-naphthalenediaminein 450 parts of 64 per cent sulphuric acid.

'The mixture is heated to boiling for from 4 to 5 hours under a refluxcondenser and then poured into water. Small amounts of impurities arefiltered oil and the filtrate is made alkaline. The 1 (N) -2,5 (N),6-dipyridinonaphthalene separates in the form of a grey mass in analmost quantitative yield. It may be crystallized from organic solvents,as for example alcohol.

Example l7 60 parts of meta-aminophenol, 600 parts of a 63 per centsulphuric acid, parts of sodium nitrobenzene sulphonate and parts of 90per cent aqueous glycerine are heated to boiling for from 5 to 6 hoursunder a reflux condenser.

After cooling the mixture, it isrendered slightly is obtained in theform of apale yellow crystalacid to congo by the addition of alkaliwhereby a dark mass is precipitated. This is filtered off and an excessof soda solution is added to the filtrate. A yellow grey mass, partly ina crystalline form, is precipitated and this is filtered off by suctionand washed until neutral. By crystallization, as for example frommono-chlorbenzene, 7-hydroxyquinoline is obtained therefrom as a productreadily soluble in alkalies and acids.

Example 18 formula separating in crystalline form and in a very goodyield is filtered oif, washed with water and dried. It is very readilysoluble in a dilute soda solution and may be recrystallized from dilutesulphuric acid and is thus obtained in fine colorless needles.

Other 2-naphthy1amino-sulphonic acids may be converted in a similarmanner into the corresponding 2-naphthoquinoline sulphonic acids.

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Example 19 300 parts of 1-naphthylamino-5-sulphonic acid are introducedinto a solution of nitrobenzene sulphonic acid prepared by warming 2'70parts of nitrobenzene with 1200 parts of a 17 per cent oleum andsubsequent dilution with 600 parts of water. After the addition of 360parts of a 90 per cent aqueous glycerine the whole is boiled under areflux condenser while stirring whereby the acid slowly passes intosolution. After a few hours the solution is diluted with from 1000 to2000 parts of water, whereby the l-naphthoquinoline-5-sulphonic acidcorresponding to the formula separates in crystalline form in aboutquantitative yield. The acid is filtered oif freed from mineral acid byWashing and dried. It is entirely insoluble in cold dilute acids andreadily soluble in dilute alkaline solutions.

Other l-naphthylamino-sulphonic acids, for example the naphthionic acidmay be converted in an analogous manner into the correspondingl-naphthoquinoline sulphonic acids.

Example 20 100 parts of crude 2,8-aminohydroxynaphthalene-fi-sulphonicacid are introduced into a solution of nitrobenzene sulphonic acidprepared by warming 90 parts of nitrobenzene with 400 parts of a 17 percent oleum and subsequent dilution with 200 parts of Water, whereupon110 parts of 90 per cent aqueous glycerine are added. The whole isboiled under a reflux condenser while stirring for a few hours, is thendiluted with from 1000 to 2000 parts of water, the8-hydr0xy-2-naphthoquinoline-G-sulphonic acid corresponding to theformula Hogs separated in crystalline form and in a very good yield,filtered off and slowly washed with hot water.

Example 21 50 parts of tetrahydro-2-naphthylamine, 600 parts of a 65 percent sulphuric acid, 140 parts of nitrobenzene sulphonic acid and 90parts of a 90 per cent aqueous glycerine are heated to boiling under areflux condenser for a few hours. After cooling the reaction mixture isdiluted with about 1000 parts of water, filtered, the filtrate renderedalkaline and extracted with ether. After evaporation of the ether theremaining oil is distilled in vacuo. The semi-solid mass Obtained is amixture of linear and angular tetrahydro-2-naphthoquinolinecorresponding to the formula:

50 parts of 3,6-diaminoacridine are introduced into a. solution ofnitrobenzene sulphonic acid prepared by warming 90 parts of nitrobenzenewith 400 parts of a 17 per cent oleum to about 100 C. and subsequentdilution with 240 parts of water, whereupon 140 parts of 90 per centaqueous glycerine are added and the whole heated to boiling under areflux condenser. The boiling point is initially at about 129 C. andfalls after about 8 to 9 hours to 127 C. After that time the reactionmixture is diluted with water and so much of alkali is added that thesolution is still slightly acid to congo, whereupon impurities which mayhave separated are filtered off. The filtrate is then rendered alkaline,whereupon the reaction oil distilled in vacuo.

product separates in grey flocks. It is filtered off, washed untilneutraland dried. The dipyridinoacridine thus obtained corresponds tothe formula '/O O\' U i U and may be recrystallized from organicsolvents Example 23 186 parts of aniline are dissolved in3200 parts of a69 per cent sulphuric acid, whereupon'160 parts of nitrobenzene and 500parts of glycerine of 28 Baum are added. The mixture is then heated toboiling while stirring under a reflux condenser. The boiling pointinitially is at about 138 C. and falls in the course of a few hours to135 C. Nitrobenzene cannot then anymore be detected. The whole is thenallowed to cool, rendered alkaline by the addition of aqueous ammoniaand distilled with steam. The distillate is acidified by means ofhydrochloric acid and concentrated by evaporation. Thequinolinehydrochloride is separated in the form of a double salt byadding zinc chloride to the concentrated solution. The salt isdecomposed in the usual manner by means of ammonia and the separated Theyield of quinoline is about 170 parts.

Ewample 24 100 parts of aniline are heated to boiling for about 24 hourswith 250 parts ofnitrobenzene sulphonic acid sodium salt, 260 parts of a90 per cent aqueous glycerine and 1450 parts of a 55 per cent sulphuricacid. The water formed during the reaction is distilled off so that theinitial boiling point of the mixture which is about 126 C. ismaintained. On working up the reaction mixture in the usual manner ayield of 84 parts of quinoline is obtained.

When raising after 16 hours the boiling point of the reaction mixture inthe above described process to about 135 C. by distilling off more waterand keeping the mixture boiling for 8 hours the yield increases to about9'? parts.

Example 25 Example 26 260 parts of nitrobenzene are sulphonated bywarming with 800 parts of a 23 per cent oleum, the mixture then beingdiluted after cooling with 250 parts of water and parts of a 1 per centaqueous solution of ammonium Vanadate. 260 parts of aniline and 500parts of an 88 per cent crude glycerine are then added to the reaction 5mixture which is heated to boiling. Care is taken that by slowlydistilling off water the boiling point which initially is 130 C. risesin the course of several hours to 165 C., the reaction mixture thenbeing kept at the said temperature for some time. The reaction mixtureis then worked up in the usual manner, whereby 269 parts of purequinoline are obtained.

What we claim is:

1. The improvement in the manufacture of pyridino compounds, whichcomprises acting on an amine of a from one to three-ringed aromaticcompound which in the case of a three- .ringed isooyclic compound shouldnot contain keto groups in para-position to each other, with glycerinein the presence of vanadium pentoxide and an aromatic nitrocompo-und'selected from the group consisting of nitrobenzene andnitrobenzene sulphonic acids, in a sulphuric acid of from 40 to per centstrength at atemperature between about and C.

2. As new article of manufacture pyridinonaphthostyril corresponding tothe formula:

crystallizing from trichlorobenzene in the form of colorless crystals.

MAX ALBERT KUNZ. GERD KOCHENDOERFER. KARL KOEBERLE.

